Since the first description of Klinefelter syndrome (KS) was published in 1942 in The Journal of Clinical Endocrinology , large inter‐individual variability in the phenotypic presentation has been demonstrated. However, our understanding of the global impact of the additional X chromosome on the genome remains an enigma. Evidence from the existing literature of KS indicates that not just one single genetic mechanism can explain the phenotype and the variable expressivity, but several mechanisms may be at play concurrently. In this review, we describe different genetic mechanisms and recent advances in the understanding of the genome, epigenome, and transcriptome of KS and the link to the phenotype and clinical heterogeneity. Future studies are needed to unite clinical data, genomic data, and basic research attempting to understand the genetics behind KS. Unraveling the genetics of KS will be of clinical relevance as it may enable the use of polygenic risk scores to predict future disease susceptibility and enable clinical risk stratification of KS patients in the future.

中文翻译：

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Klinefelter综合征的表观遗传学和基因组学。

自从1942年在《临床内分泌学杂志》上发表克氏综合征（KS）的首次描述以来，已证明表型表现存在较大的个体间差异。但是，我们对其他X染色体对基因组的全球影响的理解仍然是一个谜。KS现有文献的证据表明，不仅单一的遗传机制可以解释表型和可变表达，而且多种机制可能同时发挥作用。在这篇综述中，我们描述了不同的遗传机制和对KS的基因组，表观基因组和转录组的理解以及与表型和临床异质性的联系的最新进展。需要进一步的研究来统一临床数据，基因组数据和基础研究，以试图了解KS背后的遗传学。